Dll4-Notch signaling as a therapeutic target in tumor angiogenesis

Kuhnert, Frank; Kirshner, Jessica R.; Thurston, Gavin

doi:10.1186/2045-824x-3-20

Cited by 110 publications

(84 citation statements)

References 76 publications

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“…5D). Expression of Dll4 was strongly repressed, in agreement with the observed increased vascular density and hypoxia, but in apparent contradiction with the enhanced tumor development (24). Of note, flt-1 expression was strongly increased in 4T1-Egfl7 tumor endothelial cells, and the expression levels of CD31/PECAM, P-selectin, VE-cadherin, eNOS, and of the integrin subunits av, a3, b1, and b3 were not modified (not shown).…”

Section: Egfl7 Represses Leukocyte Adhesion Molecules In Tumor Endothsupporting

confidence: 53%

Egfl7 Promotes Tumor Escape from Immunity by Repressing Endothelial Cell Activation

et al. 2011

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Downregulating the leukocyte adhesion molecules expressed by endothelial cells that line tumor blood vessels can limit the entry of immune effector cells into the tumor mass, thereby contributing to tumoral immune escape. Egfl7 (also known as VE-statin) is a secreted protein specifically expressed by endothelial cells in normal tissues and by cancer cells in various human tumors. High levels of Egfl7 correlate with higher tumor grade and poorer prognosis. Here we show that expression of Egfl7 in breast and lung carcinoma cells accelerates tumor growth and metastasis in immunocompetent mice but not in immunodeficient mice. Tumors expressing Egfl7 were infiltrated relatively poorly by immune cells and were characterized by reduced levels of immunostimulatory cytokines ] and fewer endothelial adhesion molecules [intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)]. In vitro studies revealed that Egfl7 inhibited the expression of leukocyte adhesion molecules by endothelial cells, preventing lymphocyte adhesion. In contrast, Egfl7 did not exert any effects on immune cell activation. Human breast cancer lesions expressing high levels of Egfl7 also expressed less ICAM-1 and VCAM-1 in their blood vessels, also indicating an inverse correlation between expression levels of Egfl7 and IFN-g. Thus, Egfl7 expression in tumors promotes tumor progression by reducing the expression of endothelial molecules that mediate immune cell infiltration. Our findings highlight a novel mechanism through which tumors escape immune control. Cancer Res; 71(23); 7176-86. Ó2011 AACR.

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Section: Egfl7 Represses Leukocyte Adhesion Molecules In Tumor Endothsupporting

confidence: 53%

Egfl7 Promotes Tumor Escape from Immunity by Repressing Endothelial Cell Activation

et al. 2011

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“…S3). This is consistent with an antiangiogenic mechanism of inhibition, and is similar to what has been observed when DLL4 and VEGF inhibitors are combined (28), further suggesting that inhibition of the Notch1 and VEGF pathways is not redundant (23,24,45). Use of a Notch1 antibody may have the added advantage of simultaneously blocking oncogenic activation of Notch1 signaling not only through DLL4 in the stroma, but also through other ligands such as Jag1 or Jag2 in the tumor itself, possibly affecting prosurvival signals in addition to angiogenesis.…”

Section: Discussionsupporting

confidence: 71%

“…It has previously been demonstrated that inhibition of the Notch pathway through blockade of DLL4 can negatively affect tumor growth in preclinical models that are resistant to anti-VEGF therapy (23,24,26,28,45). To see if specific inhibition of the Notch1 receptor can achieve similar results, we used the highly vascular HT-1080 xenograft model, which has been widely used to study tumor angiogenesis.…”

Section: Treatment With 23814 Alters Tumor Vasculature and Inhibits Tmentioning

confidence: 99%

23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity

Proia

Jiang

Bell

et al. 2015

Molecular Cancer Therapeutics

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Dysregulation of Notch signaling has been implicated in the development of many different types of cancer. Notch inhibitors are being tested in the clinic, but in most cases gastrointestinal and other toxicities have limited the dosage and, therefore, the effectiveness of these therapies. Herein, we describe the generation of a monoclonal antibody against the ligand-binding domain of the Notch1 receptor that specifically blocks ligand-induced activation. This antibody, 23814, recognizes both human and murine Notch1 with similar affinity, enabling examination of the effects on both tumor and host tissue in preclinical models. 23814 blocked Notch1 function in vivo, inhibited functional angiogenesis, and inhibited tumor growth without causing gastrointestinal toxicity. The lack of toxicity allowed for combination of 23814 and the VEGFR inhibitor tivozanib, resulting in significant growth inhibition of several VEGFR inhibitor-resistant tumor models. Analysis of the gene expression profiles of an extensive collection of murine breast tumors enabled the successful prediction of which tumors were most likely to respond to the combination of 23814 and tivozanib. Therefore, the use of a specific Notch1 antibody that does not induce significant toxicity may allow combination treatment with angiogenesis inhibitors or other targeted agents to achieve enhanced therapeutic benefit. Mol Cancer Ther; 14(8); 1858–67. ©2015 AACR.

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“…Due to the role of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), endothelial cells greatly proliferate (24)(25)(26). Meanwhile, tube-like structure formation and vascular function are achieved by delta like canonical Notch ligand 4 (Dll4)/Notch-1 signaling (27)(28)(29)(30). Tumor angiogenesis is a complex process that includes multiple stages and is regulated by numerous signaling molecules that interact with one another (18).…”

Section: Introductionmentioning

confidence: 99%

Anti-angiogenic effect of arsenic trioxide in lung cancer via inhibition of endothelial cell migration, proliferation and tube formation

et al. 2017

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Abstract. Arsenic trioxide (As 2 O 3 ) exhibits a remarkable effect on leukemia treatment; however, its effect on solid tumors remains poorly explored. The present study demonstrated the inhibitory effect of As 2 O 3 on lung cancer and explored its possible mechanism. It was observed that As 2 O 3 significantly inhibited the growth of lung cancer xenografts and tumor angiogenesis in vivo. The inhibitory effect of As 2 O 3 on cell proliferation in vitro was more remarkable in vascular endothelial cells than in lung cancer cells. It was also observed that As 2 O 3 inhibited the migration of vascular endothelial cells and disrupted vascular tube formation on Matrigel assays. In addition, a series of key signaling factors involved in multiple stages of angiogenesis, including matrix metalloproteinase (MMP)-2, MMP-9, platelet-derived growth factor (PDGF)-BB/PDGF receptor-β, vascular endothelial growth factor (VEGF)-A/VEGF receptor-2, basic fibroblast growth factor (FGF)/FGF receptor-1 and delta like canonical Notch ligand 4/Notch-1, were regulated by As 2 O 3 . These findings suggested that anti-angiogenesis may be an underlying mechanism of As 2 O 3 anticancer activity in lung cancer.

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Dll4-Notch signaling as a therapeutic target in tumor angiogenesis

Cited by 110 publications

References 76 publications

Egfl7 Promotes Tumor Escape from Immunity by Repressing Endothelial Cell Activation

Egfl7 Promotes Tumor Escape from Immunity by Repressing Endothelial Cell Activation

23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity

Anti-angiogenic effect of arsenic trioxide in lung cancer via inhibition of endothelial cell migration, proliferation and tube formation

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